WO2013077822A1 - Nouvelles préparations pour le traitement du diabète - Google Patents

Nouvelles préparations pour le traitement du diabète Download PDF

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Publication number
WO2013077822A1
WO2013077822A1 PCT/TR2012/000156 TR2012000156W WO2013077822A1 WO 2013077822 A1 WO2013077822 A1 WO 2013077822A1 TR 2012000156 W TR2012000156 W TR 2012000156W WO 2013077822 A1 WO2013077822 A1 WO 2013077822A1
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WO
WIPO (PCT)
Prior art keywords
effervescent
formulation according
formulations
weight
formulation
Prior art date
Application number
PCT/TR2012/000156
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English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2013077822A1 publication Critical patent/WO2013077822A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • the present invention relates to effervescent formulations comprising pharmaceutically effective amounts of metformin and/or at least one salt thereof and use of said formulations in treatment of diabetes.
  • Diabetes is described as a metabolic disorder usually occurring due to combination of genetic and environmental factors and resulting in extremely high blood glucose level (hyperglycemia) .
  • Type 2 diabetes or, in other terms, non-insulin-dependent diabetes is the most common form of diabetes and makes up about 90% of all diabetics. In this type of diabetes, there is insufficient insulin production together with insulin resistance in surrounding tissues.
  • Type 2 diabetes is controlled by using antihyperglycemic (sugar lowering) drugs and insulin reinforcement or using both.
  • Metformin hydrochloride is an antidiabetic active agent belonging to biguanide class illustrated in the formula (I) given below;
  • the original product is GLUCOPHAGE® in tablet form and GLUCOPHAGE® in prolonged release tablet form comprising metformin hydrochloride in doses of 1000 mg, 850 mg, 500 mg.
  • Metformin hydrochloride is an active agent used in high doses and when it is mixed with other pharmaceutical excipients required for tablet obtainment, sizes of the obtained tablets are out of acceptable limits. This situation affects disintegration and dissolution rates of the final product negatively as well as leading to swallowing difficulties especially in elderly patients.
  • An alternative solution brought to this problem is the drug called RIOMET® in syrup form.
  • the dosage forms in oral solution form such as syrup have disadvantages such as difficulty of carrying, failure to determine appropriate dose, microbiological contamination.
  • WO2007038979 discloses effervescent metformin hydrochloride formulations dissolving in less than three minutes. Said effervescent formulations are characterized in that the ratio of effervescent acid to effervescent base is more than 2. These formulations comprising high amounts of effervescent acid are produced by direct compression method.
  • an excipient in a high amount for such an active agent as metformin which is used in the range of 500 to 1000 mg per dosage form.
  • active agent when active agent is used in high amount and the excipients are used in standard amounts, the dosage forms that are unsuitable for use are obtained. And this situation causes use of specific molds and different, off-size packages in production, which increases cost of production.
  • effervescent acid in the effervescent formulations given in said patent largely reduces pH value of the formulation.
  • the effervescent formulation having high acidity causes swallowing difficulties in patients due to its bitter taste.
  • the drug solution having such a low pH value damages buccal cavity and esophagus mucosa and patients have problems due to the irritation caused.
  • the present invention discloses effervescent formulations comprising pharmaceutically effective amounts of metformin or at least one pharmaceutically acceptable salt thereof.
  • One characteristic feature of the formulations of the present invention is that said formulations comprise metformin or at least one pharmaceutically acceptable salt thereof maximum 50% by weight, preferably in the range of 10 to 45% by weight, more preferably in the range of 15 to 40% by weight.
  • the active agent used in the formulations of the present invention is preferably metformin hydrochloride salt.
  • Another characteristic feature of the formulations of the present invention is to comprise at least one pharmaceutically acceptable effervescent acid in the range of 20 to 50% by weight, preferably in the range of 25 to 50% by weight, more preferably in the range of 28 to 50% by weight.
  • the pharmaceutically acceptable effervescent acids that can be used in the effervescent formulations of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and/or hydrates, anhydrates or the combinations thereof.
  • formulations of the present invention comprise at least one pharmaceutically acceptable effervescent base in the range of 10 to 40% by weight, preferably in the range of 15 to 38% by weight, more preferably in the range of 18 to 35% by weight.
  • the pharmaceutically acceptable effervescent bases that can be used in the formulations of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or combinations thereof.
  • the effervescent base comprised in the formulations is selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide and/or the combinations thereof.
  • Another characteristic feature of the formulations of the present invention is that the ratio of effervescent acid:effervescent base comprised in the formulations is in the range of 1.45:1 to 1.75:1 by weight.
  • the inventors have surprisingly found that use of effervescent acid and base in the amount given in metformin hydrochloride formulations of the present invention causes a positive change in solubility of the formulations in water.
  • the formulations of the present invention can comprise at least one other pharmaceutically acceptable excipient in addition to metformin hydrochloride, at least one effervescent acid and at least one effervescent base.
  • excipients that can be used in the formulations of the present invention can be selected from a group comprising diluents, binders, lubricants, disintegrants, anti-adhesive agents, coating agents, flavouring agents, sweeteners, colouring agents, solvents or solvent mixtures or combinations thereof.
  • the binders that can be used in the formulations of the present invention can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine, cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methylcellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol; and water or a combination thereof.
  • starches such as potato starch, corn starch, wheat starch
  • sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
  • natural and synthetic gums such as cellulose derivatives such as
  • formulations of the present invention comprise at least one pharmaceutically acceptable binder minimum 1% by weight, preferably in the range of 1 to 5% by weight, preferably in the range of 1 to 4% by weight, more preferably in the range of 1 to 3.5% by weight.
  • the disintegrants that can be used in the formulations of the present invention can be selected from a group comprising cross-linked carboxymethyl cellulose and/or its salts; cellulose derivatives such as macrocrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose; sodium starch glycolate; alginic acid; sodium alginate; chitosan; colloidal silicone dioxide; starch; pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or combinations thereof.
  • cellulose derivatives such as macrocrystalline cellulose, cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose
  • sodium starch glycolate alginic acid; sodium alginate
  • chitosan colloidal silicone dioxide
  • the lubricants that can be used in the formulations of the present invention can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminium stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohols glyceryl behenate
  • mineral oil such as sodium stearyl fumarate
  • fatty acids
  • the anti-adhesive agents that can be used in the formulations of the present invention can be selected from silicon dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.
  • the flavouring agents that can be used in the formulations of the present invention can be selected from natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, sage, eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide, 3,1- methoxy propane 1.2-diol or a combination thereof.
  • natural aroma oils such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil,
  • One characteristic feature of the formulations of the present invention is to comprise at least one pharmaceutically acceptable flavouring agent in the range of 0.1 to 1% by weight, preferably in the range of 0.25 to 1 % by weight, more preferably in the range of 0.45 to 1% by weight.
  • the sweeteners that can be used in the formulations of the present invention can be selected from sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulphame potassium, aspartame, D-tryptophan, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
  • formulations of the present invention comprise at least one pharmaceutically acceptable sweetener in the range of 0.1 to 1% by weight, preferably in the range of 0.15 to 1% by weight, more preferably in the range of 0.15 to 0.8% by weight.
  • Optimum pH value in the formulations of the present invention can be obtained in the case that the ratio of effervescent acid and effervescent base to each other is in the range of 1.5 to 2 by weight without needing to use an excipient in a high amount. Furthermore, metformin hydrochloride formulations having said pH value have easily drinkable taste after dissolved in water.
  • formulations of the present invention can be produced by any methods in the prior art such as wet granulation, dry granulation, dry blending.
  • formulations of the present invention are produced by wet granulation method.
  • Metformin formulations of the present invention can be used as combined with at least one other active agent.
  • the pharmaceutical compositions of the present invention comprising metformin hydrochloride can comprise a second active agent in addition to metformin hydrochloride.
  • the second active agent can be used in the same formulation with metformin hydrochloride formulations of the present invention though it can also be used in a different formulation and combined with metformin hydrochloride formulation of the present invention.
  • Said formulations can be in a single dosage form or in different dosage forms as a treatment package.
  • the other active agent can be formulated in any solid oral dosage forms in the prior art for instance, in the form of tablet, effervescent tablet, orodispersible tablet, controlled release tablet, prolonged release tablet, slow release tablet.
  • the pharmaceutically acceptable excipients that shall be used in order to prepare the dosage forms comprising the second active agent can be selected from the excipients given within the scope of the present invention.
  • the coating agents that can be used for film coating of the tablet formulations can be selected from lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetin, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (for instance polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatines, triethyl citrate, glyceride, titanium dioxide, yellow and/or black iron oxide, talc, sodium alginate, stearic acid, lecithin or a combination thereof.
  • One of the methods of wet granulation, dry granulation, dry blending can be used for production of the solid oral dosage forms comprising the second active agent.
  • the second active agent of the present invention can be selected from a group comprising sulfonylureas, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, DPP-IV inhibitors or the combinations thereof.
  • Sulfonylureas of the present invention can be selected from a group comprising acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glyburide, glimepiride or pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms thereof.
  • Meglitinides of the present invention can be selected from a group comprising nateglinide and repaglinide or pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms thereof.
  • Thiazolidinediones of the present invention can be selected from a group comprising rosiglitazone, rivoglitazone, pioglitazone, troglitazone or pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms thereof.
  • Alpha-glucosidase inhibitors of the present invention can be selected from a group comprising acarbose, miglitol, voglibose or pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms thereof.
  • DPP-IV inhibitors of the present invention can be selected from a group comprising sitagliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin, alogliptin or pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms thereof.
  • the effervescent metformin tablet formulation given above is prepared according to wet granulation method explained in the present invention.
  • At least one excipient and deionized water are mixed and granulation solution is
  • Metformin, repaglinide and the other excipients are mixed and the obtained mixture is wet granulated with the granulation solution obtained in the first step,
  • the two dosage forms are formulated separately for the combined product comprising nateglinide film coated tablet and metformin hydrochloride effervescent tablet.
  • the effervescent tablet formulation comprising metformin hydrochloride is produced by the production method given in the description.
  • the film coated tablet formulation comprising neteglinide is preferably produced by the method below:
  • the mixture is granulated with the granulation solution comprising deionized water and excipient combination,

Abstract

Cette invention concerne des préparations effervescentes comprenant des quantités efficaces de metformine et/ou au moins un sel de metformine, et l'utilisation desdites préparations dans le traitement du diabète.
PCT/TR2012/000156 2011-11-23 2012-09-28 Nouvelles préparations pour le traitement du diabète WO2013077822A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR2011/11590 2011-11-23
TR201111590 2011-11-23
TR201201093 2012-01-31
TR2012/1093 2012-01-31

Publications (1)

Publication Number Publication Date
WO2013077822A1 true WO2013077822A1 (fr) 2013-05-30

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PCT/TR2012/000156 WO2013077822A1 (fr) 2011-11-23 2012-09-28 Nouvelles préparations pour le traitement du diabète

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017098481A1 (fr) * 2015-12-12 2017-06-15 Steerlife India Private Limited Compositions effervescentes de metformine et leurs procédés de préparation
WO2021194446A1 (fr) * 2020-03-27 2021-09-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation en sachet comprenant de la metformine et de la dapagliflozine
US11576855B2 (en) 2014-09-17 2023-02-14 Steerlife India Private Limited Effervescent composition and method of making it

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162816A1 (en) * 1999-09-17 2003-08-28 Gatlin Marjorie Regan Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes
WO2005065663A1 (fr) * 2003-12-31 2005-07-21 Alpharma, Inc. Preparations de rosiglitazone et de metformine
CZ297247B6 (cs) * 2005-03-15 2006-10-11 Lunaria, Spol. S R. O. Farmaceutický prípravek obsahující metformin
WO2007038979A1 (fr) * 2005-09-22 2007-04-12 Swissco Development Ag Composition effervescente de metformine et comprimés et granules fabriqués à partir de cette composition
GR1007299B (el) * 2010-03-24 2011-06-06 Uni - Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε Με Δ.Τ. Uni-Pharma Αβεε, Πρωτοτυπη αναβραζουσα φαρμακευτικη συνθεση υδροχλωρικης μετφορμινης με τη μορφη δισκιου

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030162816A1 (en) * 1999-09-17 2003-08-28 Gatlin Marjorie Regan Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes
WO2005065663A1 (fr) * 2003-12-31 2005-07-21 Alpharma, Inc. Preparations de rosiglitazone et de metformine
CZ297247B6 (cs) * 2005-03-15 2006-10-11 Lunaria, Spol. S R. O. Farmaceutický prípravek obsahující metformin
WO2007038979A1 (fr) * 2005-09-22 2007-04-12 Swissco Development Ag Composition effervescente de metformine et comprimés et granules fabriqués à partir de cette composition
GR1007299B (el) * 2010-03-24 2011-06-06 Uni - Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε Με Δ.Τ. Uni-Pharma Αβεε, Πρωτοτυπη αναβραζουσα φαρμακευτικη συνθεση υδροχλωρικης μετφορμινης με τη μορφη δισκιου

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11576855B2 (en) 2014-09-17 2023-02-14 Steerlife India Private Limited Effervescent composition and method of making it
WO2017098481A1 (fr) * 2015-12-12 2017-06-15 Steerlife India Private Limited Compositions effervescentes de metformine et leurs procédés de préparation
US20180360737A1 (en) * 2015-12-12 2018-12-20 Steerlife India Private Limited Effervescent compositions of metformin and processes for preparation thereof
US11219594B2 (en) 2015-12-12 2022-01-11 Steerlife India Private Limited Effervescent compositions of metformin and processes for preparation thereof
WO2021194446A1 (fr) * 2020-03-27 2021-09-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation en sachet comprenant de la metformine et de la dapagliflozine

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